7-acyl-8-hydroxyquinolines and-hydroxyquinaldines



rates 3,113,135 7 =ACYL-8 -HYDROXYQU1NGLINES AND -HYDRUXYQU1NALDENES Ernst Hodel, Basel, gwitzerland, assignor to J. R. Geigy A.-G., Basel, Switzerland No Drawing. Filed Mar. 30, 1961, Ser. No. 99,360. Claims priority, application Switzerland Mar. 31, 1960 16 Claims. (Cl. 260-289) ire wherein R represents hydrogen or the methyl group,

X represents a halogen atom, a low molecular alkyl radical or a phenyl or benzyl radical possibly substituted by halogen atoms or low molecular alkyl groups, and

R represents an alkyl radical possibly substituted by halogen atoms or it represents a phenyl radical possibly substituted by halo-gen atoms or low molecular alkyl groups,

are obtained by reacting, in the presence of a Friedel- Crafts condensing agent, in particular aluminium chloride, 8-hydroxyquinolines substituted in the -position, of the general formula fiAR wherein R and X have the meanings given above, with an acid halide of the general formula R COHal III wherein Hal represents chlorine or bromine and R has the meaning given above, the reaction being performed in an inert organic solvent.

The compounds of the general Formula I according to the invention have an excellent fungicidal action which is superior to that of 8-hydroxyquinoline and S-hydroxyquinaldine and their salts. They are suitable as active ingredients for fungicidal agents for the most various purposes, particularly for combatting fungi in plant protection and as seed dressings as they have a good action against Fusaritrm culmorum. These compounds can also be used for the protection of organic materials as, for example, they greatly restrict the growth of Aspergzllus nzger and Penicilll'li'm expansum. The new compounds also have polyvalent b-acteriostatic properties and restrict the growth of, for example, Staphylococci, Escherichia coli, Klebsiella pneumoniae and typhus bacilli. They are also active in vitro against tubercle bacilli. They are distinguished principally, however, by their strong activity against pathogenic fungi, for which reason they are excelart ine

lently suitable for use in human and veterinary medicine as well as for technical disinfectant purposes.

Preferably nitrobenzene, tetrachloroethane and o-dichlordbenzene for example are used as inert organic solvents or diluents for the reaction according to the invention. The reaction is performed advantageously with an excess of the acid halide of the general Formula III at a raised temperature. Depending on the size and type of the radical R CO to be introduced, the suitable reaction temperature can vary between about and C. When aluminium chloride is used as condensing agent, hydrogen chloride is developed during the reaction, which development ceases on completion thereof. The end product is Worked up after removal of the diluent by steam distillation, preferably by precipitation as hydrochloride or perchlorate. The new 7-acyl-8-hydroxyquinolines are obtained from the hot aqueous solution of the latter by the addition of ammonia.

Examples of starting materials of the general Formula II are: 5"chloro-B-hydroxyquinoliue and 5-chloro-8-hydroxyquinaldine, S-bromo-8hydroxyquinoline and 5- bromo-8-hydroxyquinaldine, 5-methy1-S-hydroxyquinoline and 5 methyl-S-hydroxyquinaldine as well as 5-ethyl-, 5-propyl-, 5-isopropy1-, 5-n-butyl-, S-tert. butyland S-isobutyl-8-hydroxyquinoline and -8-hydroxyquinaldine, also 5-phenyl-, S-oenzyl-, 5-(p-chloro-phenyl)-, S-(p-chlorobenzyl)-, 5 (dichlorophenyl) 8 hydroxyquinoline and -8-hydroxyquinaldine and other halogenated S-phenyland 5-benzyl-8-hydroxyquinolines and quinaldines; also S-(p-toly-l)-8-hydroxyquinoline and -8-hydroxyquina1dine and other starting materials having al-kylated phenyl or benzyl radicals, etc.

As examples of starting material-s of the general Formula III the chlorides and bromides of the following car-boxylic acids can be mentioned: acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, as well as higher fatty acids such as lauric acid, etc., also the chlorides and bromides of halogen fatty acids such as chloroacetic acid, dichloroacetic acid, trichloroacetic acid, aor B-chloropropionic acid and ocor B-chlorobutyric acid and also chlorides and bromides of benzoic acid, of chlorobenzoic acids and toluic acids, etc.

Examples of compounds of general Formula I according to this invention are: 5-bromo-7-acetyl-8-hydroxyquinaldine, S-bromo 7 benzoyl-8hydroxyquinoline, 5- benzyl 7 acetyl 8 hydroxyquinaldine, 5-bromo-7-lauroyl 8 hydroxyquinaldine, S-tert. butyl 7 isovaleric- S-hydroxyquinoline, S-phenyl 7 trichloroacetyl 8 hydroxyquinaldine, S-brorno 7 dichloroacetyl 8 hydroxyquinaldine, S-chloro 7 oc chloropropionly 8- hydroxyquinoline, S-bromo 7 l3 chlorobutyrl-8-hy droxyquinoline, S-hexyl 7 valeroyl-8-hydroxyquinaldine, S-bromo 7 hexoyl-8-hydroxyquinoline, 5-bromo 7-benzoyl-8-hydroxyquinaldine.

Advantageous compounds according to this invention are those corresponding to general Formula I wherein R is hydrogen or methyl, X is chlorine, bromine, lower alkyl (alkyl containing 1-6 carbon atoms), phenyl or benzyl and R is an alkyl, particularly efiective is an alkyl containing 15 carbon atoms, chloro-lower alkyl containing 1-5 carbon atoms (among the chloro-lower alkyl, the mono-, diand t-r-i-chloromethyls are particularly effective, monochloromethyl being especially effective), phenyl and chlorophenyl.

The following examples further illustrate the production of the new compounds. Parts are given therein as parts by weight and their relationship to parts by volume is as that of grammes to cubic centimetres. The temperatures are in degrees centigrade.

Example 1 60 parts of acetyl chloride are added dropwise within U half an hour while stirring to a mixture of 96 p chlorohydroxyquinoline and -8 9 parts by vo anhydrous tetrachloroethane and then 195 parts of aluminium chloride are added in portions over a period of The ass is then poured into a mixture of hydroaciu and ice the solvent is removed by steam 2 hours, care being taken by cooling that the inner te m 5 The liquid wmch remains is separated from pcrature remains between and The mixture is a re n which is also formed. On cooling, the crude hythen heated until, at about 90", hydrogen chloride bogus drochloride of the compound desired separates out of the to develop. The reaction mixture is stirred at 85-90" solution. lt is purified by dissolving and allowing to until, after heating for It) hours, the development of hycrystallise from hot dilute hydrochloric acid. On adding monia at 60-70" to the hydrochloric acid solution until reaction is phenolphthalein alkaline, 5-rnethyl-7-(ocnlorob-e zoyl) 8 hydroxyquinoline precipitates.

drogen chloride ceases. The reaction can then be re- 19 garded as completed. The reaction mass is then poured into a mixture of 1008 parts of ice and 5% parts by VG; of concentrated hydrochloric acid, the tetrachl A it -titer amount of this product can be obtained from is distilled off with steam and 50 parts of 79% core oric the resin which was removed above. This is done by acid are added to the yellow solution of the hydrochloride 1 boiling the esin in dilute hydrochloric acid, dissolving of the crude 5-chloro-7-acetyl 8 hydro'yc the hydrochloride, which precipitates from the hydrotained. After cooling, the perchlorate v 'uch precip fies chloric acid solution on cooling, twice in hot hydrochloric is filtered oil under suction and Washed with a little water. acid and allowing to crystallise and then neutralising its To remove aluminum salts adhering thereto, the perhydroc c acid solution with ammonia as usual. On

n3 the combined crude products from alcohol 1 d Lien from benzene, reddish yellow crystals of 5- i 7 (o-chlorobcnzoyl)-8-hydroxyquinoline are melt at l87-188"; yield -45%.

chlorate is dissolved in a mixture of 3500 parts by volume of hot water 250' parts by volume of pure, concentrated hydrochloric acid. Tue solution is treated with a-l charcoal, filtered and the percblors crystallise out. After cooling, ye i chewing cerngounds are produced in manners gregatcd on a Biichner funnel, was Z5 to .nose given in the above examples: and again dissolved in 2609 parts by volun I 7 and 150 parts by volume or" pure, consen ated hydrodegfsss chloric acid. Ammonia is added to the solution at 70 5 2thl cev fi y q 7345 until the reaction is phenolphthalein alkaline and the 5- 30 U/Ls-llfifdmxyqllinciinfi 151453 cbloro-7-acetyl-S-hydroxyquinoline is obtained by filter- 5 y lq ing. After recrystallising once or twice alcohol, it 5- W Y q 136433 is obtained in the form of reddish yelovv crys' is which i mlib/W1g-llyflmXyillllfiolille 109111 melt at l52-154; yield 68-70%. S-chloroJ-n-butyr"l-8-hydroxyquinaldine 78-80 4: 4. 1 5 7 Q 11.- v- J "9 Example 2 lull? S-inethyl 7 acetyl-S-hydroxyquino no is obtained in U 5-11 -"1yl-7n--l;utyryl-8-hy-jroxglquinoiine 117-119 a manner analogous to Lat described in Example 1 by 5 tl y1-7-n-butyryl-S-hydroxyquinaldine 36-88 reacting parts S-GE'lSKhYI-8-l'Q/("ZIOXYC1UlIlGllIlS 5- jfl rg-7-i gg -y} 8.};ydroxyquingfine parts by volume of o-dichlorobenzenc with parts of 5 1 1 7 chigmbenzgyi) g hydwxyqugn acetyl chloride in the presence of 12% parts of aluminium 49 1-3 164-166 chloride at a temperature of 75-35 and working up as A yglroxyquinsline 79-81 fixi gs? jgm jfig f or l-w i -n ejthylJ-isovaleryl-8-bydroxyguinaldine 72-74 ngdt, at 1204,42 yie1d.s62} .16.5c% v M. nlc s-ci noio-7- p-chlorooenzoyi) o hydroxyquins onne 1185-137 Example 3 f-mletliylfi-(o chlorobenzoyl)-8-hydroxyquina- 0 58 parts of o-clslorobcnzoyl chloride are added dro t '1; "7 T 157-150 Wise within half an hour While stirring to a mixture of i 8 g i ch10! obunzoyl)I8 hydmxyqum 160 161 parts of S-chloro i8 hydroxyquinaldine and carts b r 2;; hi T1,: volume of tetrachloroethane an 120 parts of 1 r0 ymu-nyblw chluiobbnwyl) 8 hydl0xyquln 171 172 L. w O cii londe are added in 5201Lf91a$ WlLllIl 2 liour s at L 4 5 cigmbwzay iupcl ature of 10-20 (external coo inc reaction Q mixture is then heated for 12 hours at loo-110 until I; 185-107 the development of hydrogen chloride is completed. The Z I v n I L I n L L t W 5-clilo o-7- oron l-8-h/drox naldin 86-88 aCld have been added and the tetrachloroetnane 1S rci. y 3 e v V S-litlbl-7-3C lyl"8hytrlGXYQUlllOlll'lfi 122-124 moved by steam distillation. The c1 udc product which 54101.0 7 PFC 10 1., separates cannot be extracted with diluted hydrochloric 0:}; i fi g E1 2. f i 0- 167-162 acid as the hydrochloride of the slightly basic substance 5 2;, i 1 i 1",? P P EE 81-8 is hydrolysed to a great extent. The crude product, Q2 11 mpwny f 7345 the form of the free base, is therefore dissolved by exi fi f l ii f-i l 105-162 traction with benzene. After conc ntrating the benzene i f iiifil ii 107F107 solution and recrystallising the precipitated product from .1 f zi if fljjdmxyqu-ilnmine 175 177 benzene, S-chloro 7 (o-chlorobeneoyl)-8-hydroxyquin- 5 F 1 7 rilhildmxyquifloiine 141-143 aldine is obtained in the form of yellow needles which imam!I209mmhydmxyqummme 16%159 melt t 192-193"; yield 5() 55% The new active substances represented by general Example 4 Formula l have good fungicidal action in screening tests 1 F and they also possess a good fungista-tic, bacteriostatic 6i pelts or o-chlorobenzoyl chloride are added drop and bactcrz cidal action. it has been found e.g. that Wrse Within half an hour while stirring to a mixture of chloro-7-pi'onionyl 8 -hydroxyquinoline and 5-chloro-7- 47.5 arts of S-rnethyl-S-hydroxyqurnonne and 3&9- psits n-butyryl-S-iiydroxyquinoline are particularly efiective in by volume of tetrachloroethane and parts of alumininliiL ting the gro of Candida m'bz'cans, Smohylococ- 1}l;l6i"1atCUl;l3OTgEfl61%f2 (a dded giltz'llll t2 hourshat inn-cg tam; cue amass, Escize hill coll, Kt'ebsz'elt'a Pneumoniae and i vixr I w in until hydrogen chlori beg s t o iifiri icg fie mzg or fig Compound 51inenyl 7 ac?tyl s hy W s c i and git. uslry 10 dioxyc uiuciine is a very good tuoerculostatic agent.

Compounds such as, for example, -chloro-7-acetyl-8-hydroxyquinoline, 5 methyl 7 acetyl-S-hydroxyquinoline are particularly efiective in vitro as fungistatics against Aspergillus fumigatus and Microsporum canis. The compounds 5-ch1oro'7-n-butyryl-8-hydroxyquinaldine, 5- methy1-7-(p-ehlorobenzoyl)-8-hydroxyquinaidine and 5- methy1-7-(o-ehlorobenzoyl)-8-hyd-roxyquinoline are very effective as fungicides against the spores of plant-parasitic fungi such as Alternaria tenuis, F usarium culmorum; Clasterosporum etc. Among other purposes, :the compounds represented by general Formula I are also suitable for combatting downy and powdery mildew and other fungi in viticulture and fruit culture as well as on other crops and ornamental plants. Some of them have also a systemic action.

The new active ingredients can be used for the protec tion of organic substrates. They have been found particularly effective for the protection of plants and parts thereof against attack by injurious fungi either as such or combined with suitable carriers and distributing agents as well as with other fungicidally or insecticidally active substances. They can be applied direct to the plant or to the seed bed earth. They are also suitable, however, for the treatment of organic materials such as, for example, Wood, textiles, skins and leather.

What I claim is:

1. A compound of the formula wherein R is a member selected from the group consisting of hydrogen and methyl, X is a member selected from the group consisting of chlorine, bromiric, lower alkyl, phenyl and benzyl, and R is a member selected from the group consisting of alizyl, chloro-lower alkyl, phenyl and chlorophenyl. 5-ethyl-7-acety1-8-hydroxyquinoline. 5-ethyl-7-n-butyryl-S-hydroxyquinoline. 5 ethyl-7 -propionyl-B-hydroxyquinaldi-ne. 5 bromo-7-acety1-8-hydroxyquinoline. 5-chloro-7-acety1-8-hydroxyquinoline. 5-rnethyl-7-acetyl-S-hydroxyquinoline. 5-chloro-7-acetyl-8-hydroxyquinaldine S-chloro-7-u-butyryl-8-hydroxyquinoline.

5-chloro-7-n-butyryl-8-hydroxyquinaldine. 5-methy-l7-n-butyryl-8-hydroxyquinoline. 12. 5-methyl-7-(p-chlorobenzoyl) 8 -1rydroxyquinal- \ooogameoam 5-chloro-7-pr-opiony1-S-hydroxyquinoline.

. 5-pheuyl-7-acetyl-S-hydroxyquinoline.

. S-chloro-7-propionyl-S-hydroxyquinoline.

. 5-methyl7-(o-chlorobenzoyl) 8 hydroxyquino- References Cited in the file of this patent UNITED STATES PATENTS Senn Nov. 26, 1946 Bavley Jan. 27, 1948 Hodel et a1 Feb. 24, 1959 Matsumara et al.: Jour. Org. Chem, volume 25, pages 8534 (1960). 

1. A COMPOUND OF THE FORMULA 